The resent invention relates to combinations of atovaquone {2-[4-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone}, proguanil {1-(4-chlorophenyl)-5-isopropylbiguanide hydrochloride} and primaquine {(RS)-8-(4-amino-1-methylbutylamino)-6-methoxyquinoline diphosphate} which have anti-malarial activity. More specifically, the invention is concerned with the use of such combinations in the treatment and prophylaxis of Plasmodium vivax malaria.
The combination of atovaquone and proguanil for the treatment of malaria has previously been disclosed in, for example, international patent application WO9412164, the entire disclosure of which is incorporated herein by reference. The combination of atovaquone and proguanil is commercially available under the name Malarone (Registered Trade Mark of the Glaxo Wellcome group of companies) as a fixed dose combination containing 250 mg of atovaquone and 100 mg proguanil.
In order to combat drug resistance and to improve antimalarial chemotherapy, it is becoming standard practice to use combinations of more than one antimalarial, either simultaneously or sequentially. However, many such combinations are antagonistic, resulting in less effective treatment and the dosage regimens are often complicated, increasing the likelihood of patients failing to complete the treatment. Moreover, there are four species of human malaria parasites each of which may react differently to any combination of antimalarial drugs. In particular, P. vivax malaria is difficult to treat successfully because a latent form of the parasite persists in the liver after treatment with most anti-malarial drugs.
It has now surprisingly been found that by combining atovaquone, proguanil and primaquine potentiation of antimalarial activity is achieved. The invention is particularly suited to the treatment and/or prophlyaxis of P. vivax malaria
In a first aspect, the present invention provides a method for the treatment and/or prophylaxis of malaria, particularly P. vivax malaria, in mammals, including humans, which comprises administering a therapeutically effective amount of atovaquone and concomitantly or sequentially administering a therapeutically effective amount of proguanil and concomitantly or sequentially administering a therapeutically effective amount of primaquine.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word xe2x80x98comprisexe2x80x99, and variations such as xe2x80x98comprisesxe2x80x99 and xe2x80x98comprisingxe2x80x99, will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
Preferably, atovaquone and proguanil are administered concomitantly and primaquine is administered subsequently. More preferably atovaquone and proguanil are administered concomitantly in the ratio 5:2 followed by administration of primaquine. Most preferably atovaquone and proguanil are administered as the fixed dose combination Malarone followed by administration of primaquine.
Thus, in a preferred embodiment the present invention provides a method for the treatment and/or prophylaxis of malaria, particularly P. vivax malaria, in mammals, including humans, which comprises administering concomitantly a therapeutically effective amount of atovaquone and proguanil in the ratio 5:2 and sequentially administering a therapeutically effective amount of primaquine.
In a second aspect, the present invention provides the use of atovaquone for the manufacture of a medicament, for administration, either sequentially or concomitantly, with proguanil and primaquine, for the treatment and/or prophylaxis of malaria, particularly P. vivax malaria, in mammals, including humans.
In another aspect, the present invention provides the use of atovaquone and proguanil for the manufacture of a medicament for administration sequentially with primaquine, for the treatment and/or prophylaxis of malaria, particularly P. vivax malaria, in mammals, including humans.
In a preferred embodiment of this aspect, the present invention provides the use of atovaquone and proguanil in the ratio 5:2 for the manufacture of a medicament for administration sequentially with primaquine, for the treatment and/or prophylaxis of malaria, particularly P. vivax malaria, in mammals, including humans.
in a further aspect, the present invention provides the use of atovaquone, proguanil and primaquine for the manufacture of a medicament for treatment and/or prophylaxis of malaria, particularly P. vivax malaria, in mammals, including humans.
Conveniently atovaquone, proguanil and primaquine are administered concomitantly. Preferably, atovaquone, proguanil and primaquine are administered in a potentiating ratio.
Thus, according to another aspect of the present invention there is provided a combination of atovaquone, proguanil and primaquine wherein the atovaquone, proguanil and primaquine are present in a potentiating ratio.
The term xe2x80x98potentiating ratioxe2x80x99 is-used herein to indicate that atovaquone, proguanil and primaquine are present in a ratio such that the antimalarial activity of the combination is greater than that of either atovaquone, proguanil or primaquine alone or of the additive activity that would be predicted for the combination based on the activities of the individual components. Thus the individual components act synergistically in combination provided they are present in a potentiating ratio.
A potentiating ratio, which may be successfully used to treat malaria, particularly P. vivax malaria, is in the range 1-250:1-1000:1 of proguanil:atovaquone:primaquine. Suitably, the potentiating ratio is in the range 2-100:5-200:1. A particularly preferred potentiating ratio is in the range 4-30:10-75:1 .
According to a still further aspect of the present invention, there is provided a kit comprising in association for separate administration atovaquone, proguanil and primaquine. Preferably, the kit comprises atovaquone and proguanil in the ratio 5:2 and primaquine. Most preferably, the kit comprises Malarone and primaquine.
The amount of a combination of atovaquone, proguanil and primaquine required to be effective as an antimalarial agent will, of course, vary and is ultimately at the discretion of the medical or veterinary practitioner. The factors to be considered include the route of administration and nature of the formulation, the mammal""s bodyweight, age and general condition and the nature and severity of the disease to be treated. In general, a suitable effective dose for administration to man for treatment of malaria is in the range of 0.2 to 20 mg of proguanil per kilogram bodyweight per day, 2.0 mg to 100 mg of atovaquone per kilogram bodyweight per day and 0.05 mg to 10 mg of primaquine per kilogram bodyweight per day, for example from 0.5 to 15 mg/kg/day of proguanil, 4 to 50 mg/kg/day of atovaquone and 0.1mg to 5 mg/kg/day of primaquine, particularly 3 to 10 mg/kg/day of proguanil, 10 to 25 mg/kg/day of atovaquone and 0.2 to 2 mg/kg/day of primaquine. Preferably, atovaquone and proguanil are administered concomitantly for three days and primaquine is administered alone for 14 days.
A suitable effective dose for administration to man for prophylaxis of malaria is in the range of from 0.05 to 20 mg of proguanil per kilogram bodyweight per day, 0.2 to 50 mg of atovaquone per kilogram bodyweight per day and 0.05 to 10 mg of primaquine per kilogram bodyweight per day, for example from 0.1 to 10 mg/kg/day of proguanil, 0.5 to 20 mg/kg/day of atovaquone and 0.1 to 5 mg/kg/day of primaquine, particularly 0.5 to 5 mg/kg/day of proguanil, 1 to 10 mg/kg/day of atovaquone and 0.2 to 2 mg/kg/day of primaquine. Preferably, atovaquone and proguanil are administered concomitantly during exposure to malaria and for a further 7 days after exposure has ended, and primaquine is administered for 14 days after exposure to malaria has ended.
It should be understood that the dosages referred to above are calculated in terms of the drugs per se.